Specific Aim 1: Development of the Macrocyclic Enyne RCM Reaction a. Accumulation of new knowledge from a systematic study of previously unexplored macrocycle-forming enyne metathesis by developing new general substrate platforms. b. The study of ring size-dependency and substituent effect in the enyne metathesis reaction. c. Exploration of the parameters that control exo/endo-mode in ring-closure and the E/Z selectivity of the resultant cyclic 1,3-dienes. d. Mechanistic study to address one of the controversial issues in enyne metathesis regarding the initiation. Specific Aim 2: Development of a Silicon-tethered Tandem Enyne Metathesis for the Construction of Macrocyclic Carbocycles and Macrolides a. Development of silicon tether strategy for tandem enyne RCM and the efficient synthesis of silyl ethers and silaketals. b. Application of silicon-tethered tandem enyne RCM reaction to a total synthesis of (+)-cochleamycin. Specific Aim 3: Synthesis of Biogenetic Precursors of the Enediyne Core of C-1027 using Macrocyclic Enyne RCM Reaction a. Development of novel strategy based on enyne RCM reaction for the synthesis of enediyne natural products. b. The study of the reactivity and selectivity of the conjugated alkynyl alkylidenes. c. Efficient synthesis of a variety of putative biogenetic precursors of a potent antitumor agent C-1027. d. (Long-term goal) Collaborative research with Professor Ben Shen of School of Pharmacy at UW-Madison by integrating the tools for chemical synthesis and biosynthesis for the elucidation of biosynthetic pathway of enediyne natural product C-1027.